TY - JOUR
T1 - Development of 2 bromodomain and extraterminal inhibitors with distinct pharmacokinetic and pharmacodynamic profiles for the treatment of advanced malignancies a C
AU - Falchook, Gerald
AU - Rosen, Seth
AU - LoRusso, Patricia
AU - Watts, Justin
AU - Gupta, Shilpa
AU - Coombs, Catherine C.
AU - Talpaz, Moshe
AU - Kurzrock, Razelle
AU - Mita, Monica
AU - Cassaday, Ryan
AU - Harb, Wael
AU - Peguero, Julio
AU - Smith, David C.
AU - Piha-Paul, Sarina A.
AU - Szmulewitz, Russ
AU - Noel, Marcus S.
AU - Yeleswaram, Swamy
AU - Liu, Phillip
AU - Switzky, Julie
AU - Zhou, Gongfu
AU - Zheng, Fred
AU - Mehta, Amitkumar
N1 - Funding Information:
Tocagen, U.T. MD Anderson Cancer Center, and Vegenics; reports receiving speakers' bureau honoraria from Total Health Conferencing; is an unpaid consultant/advisory board member for Fujifilm; and reports receiving other remuneration from Wolters Kluwer, Bristol-Myers Squibb, EMD Serono, Fujifilm, and Millennium. P. LoRusso is an unpaid consultant/advisory board member for AbbVie, Agios, Five Prime, Halozyme, Roche-Genentech imCore Alliance, Gen-entech, CytomX, Takeda, SOTIO, Cybrexa, Agenus, Tyme, IQVIA, TRIGER, Pfizer, I-MAB, ImmunoMet, Black Diamond, Sartarius, and GlaxoSmithKline. J. Watts is an employee/paid consultant for and reports receiving speakers' bureau honoraria from Jazz Pharma; reports receiving commercial research grants from Takeda; and is an unpaid consultant/advisory board member for Celgene and Pfizer. C.C. Coombs is an employee/paid consultant for AbbVie, and is an unpaid consultant/advisory board member for Octapharma, Loxo, Pharmacyclics, H3 Biomedicine, AbbVie, and Medscape. R. Kurzrock reports receiving commercial research grants to her institution from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Foundation Medicine, Guardant Health, Grifols, Konica Minolta, DeBiopharm, Boehringer Ingelheim, and OmniSeq; reports receiving speakers' bureau honoraria from Roche; holds ownership interest (including patents) in IDbyDNA, CureMatch, and Soluventis; is an unpaid consultant/advisory board member for Gaido, LOXO, X-Biotech, Actuate Therapeutics, Roche, NeoMed, Soluventis, and Pfizer; and reports receiving other remuneration from CureMatch, IDbyDNA, and Soluventis. R. Cassaday is an employee/paid consultant for Seattle Genetics, Amgen, Pfizer, and Adaptive Biotechnologies; reports receiving commercial research grants from Amgen, Pfizer, Merck, Vanda Pharmaceuticals, and Incyte; and has immediate family members who hold ownership interest (including patents) in Seattle Genetics. D.C. Smith reports receiving commercial research grants from Incyte, Agensys, Eli Lilly, Bayer, MedImmune, Novartis, OncoMed, Seattle Genetics, Bristol-Myers Squibb/Medarex, Genentech, Medivation/Astellas, Merck, and F. Hoffman La Roche. S.A. Piha-Paul reports receiving other commercial research support through her institution from AbbVie, Aminex Therapeutics, BioMarin Pharmaceutical, Boehringer Ingelheim, Bristol-Myers Squibb, Cerulean Pharma, Chugai Pharmaceutical, Curis, Five Prime Therapeutics, Genmab A/S, GlaxoSmithKline, Helix BioPharma, Incyte, Jacobio Pharmaceuticals, MedImmune, Medivation, Merck Sharp and Dohme, NewLink Genetics/ Blue Link Pharmaceuticals, Novartis, Pieris Pharmaceuticals, Pfizer, Pume Biotechnology, Rapt Therapeutics, Seattle Genetics, Taiho Oncology, Tesaro, Trans Thera Bio, XuanZhu Biopharma. M.S. Noel is an employee/paid consultant for Celgene. S. Yeleswaram is an employee/paid consultant for and holds ownership interest (including patents) in Incyte. P. Liu is an employee/paid consultant for
Funding Information:
The authors wish to thank the patients and their families, the investigators, the site personnel who participated in these studies. The authors would also like to thank Dr. Ping Jiang (Incyte Research Institute, Incyte Corporation, Wilmington, DE) for biomarker analyses. Incyte Corporation (Wilmington, DE) sponsored these studies. Medical writing assistance was provided by Sneha DSilva, MD, and Simon J. Slater, PhD (Envision Pharma Group, Philadelphia, PA), and funded by Incyte Corporation.
PY - 2020/3/15
Y1 - 2020/3/15
N2 - Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients and Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
AB - Purpose: Bromodomain and extraterminal (BET) proteins are key epigenetic transcriptional regulators, inhibition of which may suppress oncogene expression. We report results from 2 independent first-in-human phase 1/2 dose-escalation and expansion, safety and tolerability studies of BET inhibitors INCB054329 (study INCB 54329-101; NCT02431260) and INCB057643 (study INCB 57643-101; NCT02711137). Patients and Methods: Patients (≥18 years) with advanced malignancies, ≥1 prior therapy, and adequate organ functions received oral INCB054329 (monotherapy) or INCB057643 (monotherapy or in combination with standard-of-care) in 21-day cycles (or 28-day cycles depending on standard-of-care combination). Primary endpoints were safety and tolerability. Results: Sixty-nine and 134 patients received INCB054329 and INCB057643, respectively. Study INCB 54329-101 has been completed; INCB 57643-101 is currently active, but not recruiting (no patients were receiving treatment as of January 8, 2019). Terminal elimination half-life was shorter for INCB054329 versus INCB057643 (mean [SD], 2.24 [2.03] vs. 11.1 [8.27] hours). INCB054329 demonstrated higher interpatient variability in oral clearance versus INCB057643 (CV%, 142% vs. 45.5%). Most common (>20%) any-grade treatment-related adverse events were similar for both drugs (INCB054329; INCB057643): nausea (35%; 30%), thrombocytopenia (33%; 32%), fatigue (29%; 30%), decreased appetite (26%; 22%). Two confirmed complete responses and 4 confirmed partial responses with INCB057643 were reported as best responses. Conclusions: INCB057643 exhibited a more favorable PK profile versus INCB054329; exposure-dependent thrombocytopenia was observed with both drugs which limited the target inhibition that could be safely maintained. Further efforts are required to identify patient populations that can benefit most, and an optimal dosing scheme to maximize therapeutic index.
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U2 - 10.1158/1078-0432.CCR-18-4071
DO - 10.1158/1078-0432.CCR-18-4071
M3 - Article
C2 - 31527168
AN - SCOPUS:85081941841
VL - 26
SP - 1247
EP - 1257
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 6
ER -